Potential blindness in children of patients with hereditary bone disease.

Mono- and bi-allelic mutations in the low-density lipoprotein receptor related protein 5 (LRP5) may cause osteopetrosis, autosomal dominant and recessive exudative vitreoretinopathy, juvenile osteoporosis, or persistent hyperplastic primary vitreous (PHPV). We report on a child affected with PHPV and carrying compound mutations. The father carried the splice mutation and suffered from severe bone fragility since childhood. The mother carried the missense mutation without any clinical manifestations. The genetic diagnosis of their child allowed for appropriate treatment in the father and for the detection of osteopenia in the mother. Mono- and bi-allelic mutations in LRP5 may cause osteopetrosis, autosomal dominant and recessive exudative vitreoretinopathy, juvenile osteoporosis, or PHPV. PHPV is a component of persistent fetal vasculature of the eye, characterized by highly variable expressivity and resulting in a wide spectrum of anterior and/or posterior congenital developmental defects, which may lead to blindness. We evaluated a family diagnosed with PHPV in their only child. The child presented photophobia during the first 3 weeks of life, followed by leukocoria at 2 months of age. Molecular resequencing of NDP, FZD4, and LRP5 was performed in the child and segregation of the observed mutations in the parents. At presentation, fundus examination of the child showed a retrolental mass in the right eye. Ultrasonography revealed retinal detachment in both eyes. Thorough familial analysis revealed that the father suffered from many fractures since childhood without specific fragility bone diagnosis, treatment, or management. The mother was asymptomatic. Molecular analysis in the proband identified two mutations: a c.[2091+2T>C] splice mutation and c.[1682C>T] missense mutation. We report the case of a child affected with PHPV and carrying compound heterozygous LRP5 mutations. This genetic diagnosis allowed the clinical diagnosis of the bone problem to be made in the father, resulting in better management of the family. It also enabled preventive treatment to be prescribed for the mother and accurate genetic counseling to be provided.

Molecular Analysis of NOTCH2 in Patients with Primary Open-Angle Glaucoma.

BACKGROUND AND PURPOSE: Transgenic mice overexpressing Notch2 in the uvea exhibit a hyperplastic ciliary body leading to increased IOP and glaucoma. The aim of this study was to investigate the possible presence of NOTCH2 variants in patients with primary open-angle glaucoma (POAG). METHODS: We screened DNA samples from 130 patients with POAG for NOTCH2 variants by denaturing high-performance liquid chromatography after PCR amplification and validated our data by direct Sanger sequencing. RESULTS: No mutations were observed in the coding regions of NOTCH2 or in the splice sites. 19 known SNPs (single nucleotide polymorphisms) were detected. An SNP located in intron 24, c.[4005+45A>G], was seen in 28.5% of the patients (37/130 patients). As this SNP is reported to have a minor allele frequency of 7% in the 1000 genomes database, it could be associated with POAG. However, we evaluated its frequency in an ethnic-matched control group of 96 subjects unaffected by POAG and observed a frequency of 29%, indicating that it was not related to POAG. CONCLUSION: NOTCH2 seemed to be a good candidate for POAG as it is expressed in the anterior segment in the human eye. However, mutational analysis did not show any causative mutation. This study also shows that proper ethnic-matched control groups are essential in association studies and that values given in databases are sometimes misleading.